Purpose: Breast cancer is the second leading cancer type among people of advanced countries. Vari... more Purpose: Breast cancer is the second leading cancer type among people of advanced countries. Various methods have been used for cancer treatment such as chemotherapy and radiotherapy. In the present study we have designed and synthesized a new group of drug delivery systems (DDS) containing a new class of Cell Penetrating Peptides (CPPs) named Peptide Amphiphiles (PAs). Methods: Two PAs and anionic peptides were synthesized using solid phase peptide synthesis (SPPS), namely [KW]4, [KW]5, E4 and E8. Then nano-peptides were synthesized by non-covalent binding between PAs and poly anions as [KW]4-E4, [KW]4-E8, [KW]5-E4 and [KW]5-E8. Results: Flow cytometry studies showed that increased chain length of PAs with a higher ratio between hydrophobicity and net charge results in increased intracellular uptake by MCF7 cells after 2h incubation. Moreover, nano-peptides showed greater intracellular uptake compared to PAs. Anti-proliferative assay revealed that by increasing chain length of PAs, the toxicity effect on MCF7 cells is reduced, however nano-peptides did not show significant toxicity on MCF7 cells even at high concentration levels. Conclusion: These data suggest that due to the lack of toxicity effect at high concentration levels and also high cellular uptake, nano-peptides are more suitable carrier compared to PAs for drug delivery.
Artificial Cells Nanomedicine and Biotechnology, Sep 21, 2017
A new class of cell penetrating peptides (CPPs) named peptide amphiphile was designed to improve ... more A new class of cell penetrating peptides (CPPs) named peptide amphiphile was designed to improve the intracellular uptake and the antitumor activity of epirubicin (EPR). Various amphiphilic CPPs were synthesized by solid phase peptide synthesis method and were chemically conjugated to EPR. Their corresponding nanoparticles (CPPs-E4 and CPPs-E8) were prepared via non-covalent binding of the peptides and polyanions. Cytotoxicity and anti-proliferative activity were evaluated by MTT assay. Cellular uptake was examined by flow cytometry and fluorescence microscopy. The CPPs exhibited slight cytotoxicity. Binding of polyglutamate to CPPs (CPPs-E4 and CPPs-E8 nanoparticles) decreased their cytotoxicity. CPPs-E8 nanoparticles showed lower cytotoxicity than CPPs-E4 nanoparticles. Cellular uptake of K3W4K3-E8, K2W4K2-E8 and W3K4W3-E8 reached 100% with no difference between each of the mentioned CPPs and its nanoparticles at 50 mM. The anti-proliferative activity of EPR was enhanced following conjugation to peptides and nanoparticles at 25 mM. CPPs-EPR-E4 and CPPs-E8-EPR nanoparticles displayed higher anti-proliferative activity than CPPs-EPR at 25 mM. CPPs-E8-EPR nanoparticles showed higher anti-proliferative activity than CPPs-E4-EPR. K3W4K3-E8-EPR nanoparticles exhibited the highest anti-proliferative activity at 25 mM. The synthesized peptide nanoparticles are proposed as suitable carriers for improving the intracellular delivery of EPR into tumor cells with low cytotoxicity and high antitumor activity.
Drug Development and Industrial Pharmacy, Mar 5, 2020
The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challeng... more The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challenge for efficient cancer therapy. Self-assembled peptide nanoparticles (SAPNs) are one of the major classes of peptide vectors that have gained much of attention towards novel drug delivery systems. In the present study, different sequences of cell penetrating peptides including R2W4R2 and W3R4W3 and their SAPNs (R2W4R2-E12 and W3R4W3-E12) were designed for efficient delivery of MTX into MCF7 breast cancer cells. Based on electron microscopy results, the obtained SAPNs were in nano scale with spherical shape. There was a positive relationship between the free energy of water to octanol transferring and cellular penetration of designed nanostructures. The R2W4R2 possessed proper free energy and ability to form a spherical structure and hydrophobic-hydrophobic interactions, therefore, exhibited more cellular penetration than W3R4W3. The cellular uptake of obtained nanoparticles was examined by flow cytometry and fluorescence microscopy, in which, R2W4R2 and R2W4R2-E12 showed more appropriate penetration into MCF7 cells than W3R4W3 and W3R4W3-E12. The cytotoxicity of MTX-loaded peptides and SAPNs were examined by MTT assay. As a result, at higher concentrations, the R2W4R2 and R2W4R2-E12 showed higher cytotoxic behavior than their counterparts. Despite their enhanced cellular internalization, the cytotoxic behavior of MTX-loaded SAPNs at lower concentrations was relatively less than free MTX, which could be ascribed to the gradual nature of drug detachment from these conjugates. Therefore, R2W4R2 could be considered as an efficient choice to enhance the therapeutic efficiency of MTX in cancer treatments.
Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various mol... more Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP‐peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly‐glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.
Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to tre... more Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to treat many types of solid tumors. However, it has many limitations such as a short plasma half-life, dose-limiting toxicities and drug resistance. Cell-penetrating peptides (CPPs) are short peptides which may deliver a large variety of cargo molecules into the cancerous cells. The current study was designed to evaluate the antiproliferative activity of gemcitabine chemically conjugated to CPPs. The peptides were synthesized using solid phase synthesis procedure. The uptake efficiency of CPPs into cells was examined by flow cytometry and fluorescent microscopy. The synthesized peptides were chemically conjugated to Gem and the in vitro cytotoxicity of conjugates was tested by MTT assay on A594 cell line. According to the obtained results, cellular uptake was increased with increasing the concentration of CPPs. On the other hand the coupling of Gem with peptides containing block sequence of arginine (R5W3R4) and some alternating sequences (i.e. [RW]6 and [RW]3) exhibited improved antitumor activity of the drug. The findings in this study support the advantages of using cell-penetrating peptides for improving intracellular delivery of Gem into tumor as well as its activity.
Journal of Drug Delivery Science and Technology, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
6Th National First International Iranian Stroke Congress, Nov 27, 2013
Introduction Neuroinflammation following acute stroke is seemed to play a major role in secondary... more Introduction Neuroinflammation following acute stroke is seemed to play a major role in secondary brain injury and compromised microvascular perfusion. Central to this process is the enhance expression of P- and E-selectin in activated endothelium following ischemia/reperfusion. Although the inhibition of selectin adhesion molecules attenuates infarct-related damage, neuroinflammation is a process with each tissue, brain region and individual potentially having its own timing and magnitude of response. Because of this inherent complexity, critical aspects of the early evolution of stroke injury are poorly understood. Thus, there is a great need to study the progression of neuroinflammation and endothelial activation non-invasively that helpful in selecting and monitoring patients who may benefit from such therapy. Now MRI can be applicated to follow the evolution of stroke-related brain injury but it cannot discriminate pathological processes such as inflammation. The solution of this problem is to use MRI to visualize endothelial activation by using magnetic iron oxide nanoparticles (IO). IO nanoparticles have a long blood retention time, biodegradability and low toxicity and a large surface area that can be engineered to provide a large number of functional groups for example agent (MNP-Psel) that was modified to bind with high affinity to P-selectin. Conclusion IO nanoparticles possess unique paramagnetic properties, which create considerable susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for MRI, which is used to help to more specifically target antiinflammatory early diagnosis and therapy in patients with stroke.
The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challeng... more The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challenge for efficient cancer therapy. Self-assembled peptide nanoparticles (SAPNs) are one of the major classes of peptide vectors that have gained much of attention towards novel drug delivery systems. In the present study, different sequences of cell penetrating peptides including R2W4R2 and W3R4W3 and their SAPNs (R2W4R2-E12 and W3R4W3-E12) were designed for efficient delivery of MTX into MCF7 breast cancer cells. Based on electron microscopy results, the obtained SAPNs were in nano scale with spherical shape. There was a positive relationship between the free energy of water to octanol transferring and cellular penetration of designed nanostructures. The R2W4R2 possessed proper free energy and ability to form a spherical structure and hydrophobic-hydrophobic interactions, therefore, exhibited more cellular penetration than W3R4W3. The cellular uptake of obtained nanoparticles was examined by flow cytometry and fluorescence microscopy, in which, R2W4R2 and R2W4R2-E12 showed more appropriate penetration into MCF7 cells than W3R4W3 and W3R4W3-E12. The cytotoxicity of MTX-loaded peptides and SAPNs were examined by MTT assay. As a result, at higher concentrations, the R2W4R2 and R2W4R2-E12 showed higher cytotoxic behavior than their counterparts. Despite their enhanced cellular internalization, the cytotoxic behavior of MTX-loaded SAPNs at lower concentrations was relatively less than free MTX, which could be ascribed to the gradual nature of drug detachment from these conjugates. Therefore, R2W4R2 could be considered as an efficient choice to enhance the therapeutic efficiency of MTX in cancer treatments.
Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to tre... more Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to treat many types of solid tumors. However, it has many limitations such as a short plasma half-life, dose-limiting toxicities and drug resistance. Cell-penetrating peptides (CPPs) are short peptides which may deliver a large variety of cargo molecules into the cancerous cells. The current study was designed to evaluate the antiproliferative activity of gemcitabine chemically conjugated to CPPs. The peptides were synthesized using solid phase synthesis procedure. The uptake efficiency of CPPs into cells was examined by flow cytometry and fluorescent microscopy. The synthesized peptides were chemically conjugated to Gem and the in vitro cytotoxicity of conjugates was tested by MTT assay on A594 cell line. According to the obtained results, cellular uptake was increased with increasing the concentration of CPPs. On the other hand the coupling of Gem with peptides containing block sequence of a...
Despite the extensive application of methotrexate (MTX) as a chemotherapeutic agent and an immune... more Despite the extensive application of methotrexate (MTX) as a chemotherapeutic agent and an immune system suppressor, its therapeutic implementation has been limited due to its poor pharmacokinetics, saturable cellular transport, and insufficient response in some conditions. These limitations have resulted in the development of novel formulations. A pH-dependent MTX release was indicated in our previous study on polyethyleneimine nano-hydrogels; however, it exhibited a fast drug release in phosphate-buffered saline simulating physiologic pH and tonicity conditions. Thus, the current study was aimed at the synthesis of Zn(MTX)2Cl2 complex (MTX-Zn) to modulate drug loading and release under physiologic condition (pH=7.4). MTX-Zn was synthesized by the hydrothermal method and characterized by TLC, FT-IR spectroscopy, and Eriochrome Black T complexometric titration. MTX-Zn was then loaded into the nano-hydrogels and purified through ultrafiltration. The final product was evaluated by DLS...
delivery of irinotecan active metabolite (SN38) in murine colorectal carcinoma through conjugatio... more delivery of irinotecan active metabolite (SN38) in murine colorectal carcinoma through conjugation to poly (2-ethyl 2-oxazoline)-b-poly (L-glutamic acid) double hydrophilic copolymer, European Journal of Pharmaceutical Sciences,
Block ionomer micellar nanoparticles from double hydrophilic copolymers, classifications and prom... more Block ionomer micellar nanoparticles from double hydrophilic copolymers, classifications and promises for delivery of cancer chemotherapeutics
In the past decade, miRNAs have been extensively attracted the scientist's attentions as ... more In the past decade, miRNAs have been extensively attracted the scientist's attentions as tumor suppressors or oncogenes that have been implicated in tumor progression, metastasis and intrinsic resistance to various cancer therapies. microRNA-21 (miR-21) demonstrates a potential oncogenic function and target tumor inhibitor proteins in almost all types of cancer. miR-21 overexpression has been studied in terms of cell proliferation, migration, invasion, metastasis, and apoptosis regulation.Inhibition of miRNA expression using antisense technology by various nanovectors of different sizes, shapes and compositions has been evolved progressively to overcome the barriers confronted by miRNA delivery.Application of miR-21 antisense oligonucleotides for treating cancerous cells has become a promising achievement for cancer therapy. Moreover,miR-21 can mediate resistance to radiation and chemotherapy. The expanding role of miR-21 functions in human cancers with an emphasis on its regulatory targets and mechanisms, miR-21 related achievements against cancer promotion have been discussed.
Artificial Cells, Nanomedicine, and Biotechnology, 2017
(2017) Synthesis and cellular characterization of various nano-assemblies of cell penetrating pep... more (2017) Synthesis and cellular characterization of various nano-assemblies of cell penetrating peptide-epirubicin-polyglutamate conjugates for the enhancement of antitumor activity. Artificial Cells, Nanomedicine, and Biotechnology. pp. 1-14.
Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGyl... more Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-l-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by (1)H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77-83nm and a relatively high drug loading (54±4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo.
Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various mol... more Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP-peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly-glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.
Cell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo int... more Cell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo into living cells. In this paper, we investigated the relationship between the structural/physicochemical properties of four new synthetic peptides containing arginine-tryptophan in terms of their cell membrane penetration efficiency. The peptides were prepared using solid phase synthesis procedure using FMOC protected amino acids. Fluorescence-activated cell sorting and fluorescence imaging were used to evaluate uptake efficiency. Prediction of the peptide secondary structure and estimation of physicochemical properties was performed using the GOR V method and MPEx 3.2 software (Wimley-White scale, helical wheel projection and total hydrophobic moment). Our data showed that the uptake efficiency of peptides with two tryptophans at the C- and N-terminus were significantly higher (about 4-fold) than that of peptides containing three tryptophans at both ends. The distribution of arginine at both ends also increased the uptake efficiency 2.52- and 7.18-fold, compared with arginine distribution at the middle of peptides. According to the obtained results the value of transfer free energies of peptides from the aqueous phase to membrane bilayer could be a good predictor for the cellular uptake efficiency of CPPs.
Breast cancer is the second leading cancer type among people of advanced countries. Various metho... more Breast cancer is the second leading cancer type among people of advanced countries. Various methods have been used for cancer treatment such as chemotherapy and radiotherapy. In the present study we have designed and synthesized a new group of drug delivery systems (DDS) containing a new class of Cell Penetrating Peptides (CPPs) named Peptide Amphiphiles (PAs). Two PAs and anionic peptides were synthesized using solid phase peptide synthesis (SPPS), namely [KW]4, [KW]5, E4 and E8. Then nano-peptides were synthesized by non-covalent binding between PAs and poly anions as [KW]4-E4, [KW]4-E8, [KW]5-E4 and [KW]5-E8. Flow cytometry studies showed that increased chain length of PAs with a higher ratio between hydrophobicity and net charge results in increased intracellular uptake by MCF7 cells after 2h incubation. Moreover, nano-peptides showed greater intracellular uptake compared to PAs. Anti-proliferative assay revealed that by increasing chain length of PAs, the toxicity effect on MCF...
Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficul... more Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described.
Purpose: Breast cancer is the second leading cancer type among people of advanced countries. Vari... more Purpose: Breast cancer is the second leading cancer type among people of advanced countries. Various methods have been used for cancer treatment such as chemotherapy and radiotherapy. In the present study we have designed and synthesized a new group of drug delivery systems (DDS) containing a new class of Cell Penetrating Peptides (CPPs) named Peptide Amphiphiles (PAs). Methods: Two PAs and anionic peptides were synthesized using solid phase peptide synthesis (SPPS), namely [KW]4, [KW]5, E4 and E8. Then nano-peptides were synthesized by non-covalent binding between PAs and poly anions as [KW]4-E4, [KW]4-E8, [KW]5-E4 and [KW]5-E8. Results: Flow cytometry studies showed that increased chain length of PAs with a higher ratio between hydrophobicity and net charge results in increased intracellular uptake by MCF7 cells after 2h incubation. Moreover, nano-peptides showed greater intracellular uptake compared to PAs. Anti-proliferative assay revealed that by increasing chain length of PAs, the toxicity effect on MCF7 cells is reduced, however nano-peptides did not show significant toxicity on MCF7 cells even at high concentration levels. Conclusion: These data suggest that due to the lack of toxicity effect at high concentration levels and also high cellular uptake, nano-peptides are more suitable carrier compared to PAs for drug delivery.
Artificial Cells Nanomedicine and Biotechnology, Sep 21, 2017
A new class of cell penetrating peptides (CPPs) named peptide amphiphile was designed to improve ... more A new class of cell penetrating peptides (CPPs) named peptide amphiphile was designed to improve the intracellular uptake and the antitumor activity of epirubicin (EPR). Various amphiphilic CPPs were synthesized by solid phase peptide synthesis method and were chemically conjugated to EPR. Their corresponding nanoparticles (CPPs-E4 and CPPs-E8) were prepared via non-covalent binding of the peptides and polyanions. Cytotoxicity and anti-proliferative activity were evaluated by MTT assay. Cellular uptake was examined by flow cytometry and fluorescence microscopy. The CPPs exhibited slight cytotoxicity. Binding of polyglutamate to CPPs (CPPs-E4 and CPPs-E8 nanoparticles) decreased their cytotoxicity. CPPs-E8 nanoparticles showed lower cytotoxicity than CPPs-E4 nanoparticles. Cellular uptake of K3W4K3-E8, K2W4K2-E8 and W3K4W3-E8 reached 100% with no difference between each of the mentioned CPPs and its nanoparticles at 50 mM. The anti-proliferative activity of EPR was enhanced following conjugation to peptides and nanoparticles at 25 mM. CPPs-EPR-E4 and CPPs-E8-EPR nanoparticles displayed higher anti-proliferative activity than CPPs-EPR at 25 mM. CPPs-E8-EPR nanoparticles showed higher anti-proliferative activity than CPPs-E4-EPR. K3W4K3-E8-EPR nanoparticles exhibited the highest anti-proliferative activity at 25 mM. The synthesized peptide nanoparticles are proposed as suitable carriers for improving the intracellular delivery of EPR into tumor cells with low cytotoxicity and high antitumor activity.
Drug Development and Industrial Pharmacy, Mar 5, 2020
The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challeng... more The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challenge for efficient cancer therapy. Self-assembled peptide nanoparticles (SAPNs) are one of the major classes of peptide vectors that have gained much of attention towards novel drug delivery systems. In the present study, different sequences of cell penetrating peptides including R2W4R2 and W3R4W3 and their SAPNs (R2W4R2-E12 and W3R4W3-E12) were designed for efficient delivery of MTX into MCF7 breast cancer cells. Based on electron microscopy results, the obtained SAPNs were in nano scale with spherical shape. There was a positive relationship between the free energy of water to octanol transferring and cellular penetration of designed nanostructures. The R2W4R2 possessed proper free energy and ability to form a spherical structure and hydrophobic-hydrophobic interactions, therefore, exhibited more cellular penetration than W3R4W3. The cellular uptake of obtained nanoparticles was examined by flow cytometry and fluorescence microscopy, in which, R2W4R2 and R2W4R2-E12 showed more appropriate penetration into MCF7 cells than W3R4W3 and W3R4W3-E12. The cytotoxicity of MTX-loaded peptides and SAPNs were examined by MTT assay. As a result, at higher concentrations, the R2W4R2 and R2W4R2-E12 showed higher cytotoxic behavior than their counterparts. Despite their enhanced cellular internalization, the cytotoxic behavior of MTX-loaded SAPNs at lower concentrations was relatively less than free MTX, which could be ascribed to the gradual nature of drug detachment from these conjugates. Therefore, R2W4R2 could be considered as an efficient choice to enhance the therapeutic efficiency of MTX in cancer treatments.
Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various mol... more Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP‐peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly‐glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.
Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to tre... more Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to treat many types of solid tumors. However, it has many limitations such as a short plasma half-life, dose-limiting toxicities and drug resistance. Cell-penetrating peptides (CPPs) are short peptides which may deliver a large variety of cargo molecules into the cancerous cells. The current study was designed to evaluate the antiproliferative activity of gemcitabine chemically conjugated to CPPs. The peptides were synthesized using solid phase synthesis procedure. The uptake efficiency of CPPs into cells was examined by flow cytometry and fluorescent microscopy. The synthesized peptides were chemically conjugated to Gem and the in vitro cytotoxicity of conjugates was tested by MTT assay on A594 cell line. According to the obtained results, cellular uptake was increased with increasing the concentration of CPPs. On the other hand the coupling of Gem with peptides containing block sequence of arginine (R5W3R4) and some alternating sequences (i.e. [RW]6 and [RW]3) exhibited improved antitumor activity of the drug. The findings in this study support the advantages of using cell-penetrating peptides for improving intracellular delivery of Gem into tumor as well as its activity.
Journal of Drug Delivery Science and Technology, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
6Th National First International Iranian Stroke Congress, Nov 27, 2013
Introduction Neuroinflammation following acute stroke is seemed to play a major role in secondary... more Introduction Neuroinflammation following acute stroke is seemed to play a major role in secondary brain injury and compromised microvascular perfusion. Central to this process is the enhance expression of P- and E-selectin in activated endothelium following ischemia/reperfusion. Although the inhibition of selectin adhesion molecules attenuates infarct-related damage, neuroinflammation is a process with each tissue, brain region and individual potentially having its own timing and magnitude of response. Because of this inherent complexity, critical aspects of the early evolution of stroke injury are poorly understood. Thus, there is a great need to study the progression of neuroinflammation and endothelial activation non-invasively that helpful in selecting and monitoring patients who may benefit from such therapy. Now MRI can be applicated to follow the evolution of stroke-related brain injury but it cannot discriminate pathological processes such as inflammation. The solution of this problem is to use MRI to visualize endothelial activation by using magnetic iron oxide nanoparticles (IO). IO nanoparticles have a long blood retention time, biodegradability and low toxicity and a large surface area that can be engineered to provide a large number of functional groups for example agent (MNP-Psel) that was modified to bind with high affinity to P-selectin. Conclusion IO nanoparticles possess unique paramagnetic properties, which create considerable susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for MRI, which is used to help to more specifically target antiinflammatory early diagnosis and therapy in patients with stroke.
The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challeng... more The low cellular uptake of Methotrexate (MTX), a commonly used anticancer drug, is a big challenge for efficient cancer therapy. Self-assembled peptide nanoparticles (SAPNs) are one of the major classes of peptide vectors that have gained much of attention towards novel drug delivery systems. In the present study, different sequences of cell penetrating peptides including R2W4R2 and W3R4W3 and their SAPNs (R2W4R2-E12 and W3R4W3-E12) were designed for efficient delivery of MTX into MCF7 breast cancer cells. Based on electron microscopy results, the obtained SAPNs were in nano scale with spherical shape. There was a positive relationship between the free energy of water to octanol transferring and cellular penetration of designed nanostructures. The R2W4R2 possessed proper free energy and ability to form a spherical structure and hydrophobic-hydrophobic interactions, therefore, exhibited more cellular penetration than W3R4W3. The cellular uptake of obtained nanoparticles was examined by flow cytometry and fluorescence microscopy, in which, R2W4R2 and R2W4R2-E12 showed more appropriate penetration into MCF7 cells than W3R4W3 and W3R4W3-E12. The cytotoxicity of MTX-loaded peptides and SAPNs were examined by MTT assay. As a result, at higher concentrations, the R2W4R2 and R2W4R2-E12 showed higher cytotoxic behavior than their counterparts. Despite their enhanced cellular internalization, the cytotoxic behavior of MTX-loaded SAPNs at lower concentrations was relatively less than free MTX, which could be ascribed to the gradual nature of drug detachment from these conjugates. Therefore, R2W4R2 could be considered as an efficient choice to enhance the therapeutic efficiency of MTX in cancer treatments.
Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to tre... more Gemcitabine (Gem) is used as a single agent or in combination with other anticancer agents to treat many types of solid tumors. However, it has many limitations such as a short plasma half-life, dose-limiting toxicities and drug resistance. Cell-penetrating peptides (CPPs) are short peptides which may deliver a large variety of cargo molecules into the cancerous cells. The current study was designed to evaluate the antiproliferative activity of gemcitabine chemically conjugated to CPPs. The peptides were synthesized using solid phase synthesis procedure. The uptake efficiency of CPPs into cells was examined by flow cytometry and fluorescent microscopy. The synthesized peptides were chemically conjugated to Gem and the in vitro cytotoxicity of conjugates was tested by MTT assay on A594 cell line. According to the obtained results, cellular uptake was increased with increasing the concentration of CPPs. On the other hand the coupling of Gem with peptides containing block sequence of a...
Despite the extensive application of methotrexate (MTX) as a chemotherapeutic agent and an immune... more Despite the extensive application of methotrexate (MTX) as a chemotherapeutic agent and an immune system suppressor, its therapeutic implementation has been limited due to its poor pharmacokinetics, saturable cellular transport, and insufficient response in some conditions. These limitations have resulted in the development of novel formulations. A pH-dependent MTX release was indicated in our previous study on polyethyleneimine nano-hydrogels; however, it exhibited a fast drug release in phosphate-buffered saline simulating physiologic pH and tonicity conditions. Thus, the current study was aimed at the synthesis of Zn(MTX)2Cl2 complex (MTX-Zn) to modulate drug loading and release under physiologic condition (pH=7.4). MTX-Zn was synthesized by the hydrothermal method and characterized by TLC, FT-IR spectroscopy, and Eriochrome Black T complexometric titration. MTX-Zn was then loaded into the nano-hydrogels and purified through ultrafiltration. The final product was evaluated by DLS...
delivery of irinotecan active metabolite (SN38) in murine colorectal carcinoma through conjugatio... more delivery of irinotecan active metabolite (SN38) in murine colorectal carcinoma through conjugation to poly (2-ethyl 2-oxazoline)-b-poly (L-glutamic acid) double hydrophilic copolymer, European Journal of Pharmaceutical Sciences,
Block ionomer micellar nanoparticles from double hydrophilic copolymers, classifications and prom... more Block ionomer micellar nanoparticles from double hydrophilic copolymers, classifications and promises for delivery of cancer chemotherapeutics
In the past decade, miRNAs have been extensively attracted the scientist's attentions as ... more In the past decade, miRNAs have been extensively attracted the scientist's attentions as tumor suppressors or oncogenes that have been implicated in tumor progression, metastasis and intrinsic resistance to various cancer therapies. microRNA-21 (miR-21) demonstrates a potential oncogenic function and target tumor inhibitor proteins in almost all types of cancer. miR-21 overexpression has been studied in terms of cell proliferation, migration, invasion, metastasis, and apoptosis regulation.Inhibition of miRNA expression using antisense technology by various nanovectors of different sizes, shapes and compositions has been evolved progressively to overcome the barriers confronted by miRNA delivery.Application of miR-21 antisense oligonucleotides for treating cancerous cells has become a promising achievement for cancer therapy. Moreover,miR-21 can mediate resistance to radiation and chemotherapy. The expanding role of miR-21 functions in human cancers with an emphasis on its regulatory targets and mechanisms, miR-21 related achievements against cancer promotion have been discussed.
Artificial Cells, Nanomedicine, and Biotechnology, 2017
(2017) Synthesis and cellular characterization of various nano-assemblies of cell penetrating pep... more (2017) Synthesis and cellular characterization of various nano-assemblies of cell penetrating peptide-epirubicin-polyglutamate conjugates for the enhancement of antitumor activity. Artificial Cells, Nanomedicine, and Biotechnology. pp. 1-14.
Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGyl... more Self-assembled nanogels were engineered by forming Zn(2+)-coordinated micellar templates of PEGylated poly ethyleneimine (PEG-g-PEI), chemical crosslinking and subsequent removal of the metal ion. Creation of stable micellar templates is a crucial step for preparing the nanogels. To this aim, imidazole moieties were introduced to the polymer by Fmoc-l-histidine using carbodiimide chemistry. It was hypothesized the nanogels loaded with methotrexate (MTX), a chemotherapeutic agent, circumvent impaired carrier activity in HepG2 cells (MTX-resistant hepatocellular carcinoma). So, the nanogels were post-loaded with MTX and characterized by (1)H-NMR, FTIR, dynamic light scattering-zeta potential, atomic force microscopy, and drug release experiments. Cellular uptake and the antitumor activity of MTX-loaded nanogels were investigated by flow cytometry and MTT assay. Discrete, spherical and uniform nanogels, with sizes about 77-83nm and a relatively high drug loading (54±4% w/w), showed a low polydispersity and neutral surface charges. The MTX-loaded nanogels, unlike empty nanogels, lowered viability of HepG2 cells; the nanogels demonstrated cell-cycle arrest and apoptosis comparably higher than MTX as free drug that was shown to be through i) cellular uptake of the nanogels by clathrin-mediated transport and ii) endosomolytic activity of the nanogels in HepG2 cells. These findings indicate the potential antitumor application of this preparation, which has to be investigated in-vivo.
Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various mol... more Cell penetrating peptides (CPPs) were developed as vehicles for efficient delivery of various molecules. An ideal CPP-peptide should not display any toxicity against cancer cells as well as healthy cells and efficiently enter into the cell. Because of the cationic nature and the intrinsic vector capabilities, these peptides can cause cytotoxicity. One of the possible reasons for toxicity of CPPs is direct translocation and consequently, pore formation on the plasma membrane. In this study it was demonstrated that interaction of poly-glutamate with CPP considerably reduced their cytotoxicity in A549 cell. This strategy could be useful for efficient drug delivery mediated by CPP.
Cell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo int... more Cell-penetrating peptides (CPPs) are used for delivering drugs and other macromolecular cargo into living cells. In this paper, we investigated the relationship between the structural/physicochemical properties of four new synthetic peptides containing arginine-tryptophan in terms of their cell membrane penetration efficiency. The peptides were prepared using solid phase synthesis procedure using FMOC protected amino acids. Fluorescence-activated cell sorting and fluorescence imaging were used to evaluate uptake efficiency. Prediction of the peptide secondary structure and estimation of physicochemical properties was performed using the GOR V method and MPEx 3.2 software (Wimley-White scale, helical wheel projection and total hydrophobic moment). Our data showed that the uptake efficiency of peptides with two tryptophans at the C- and N-terminus were significantly higher (about 4-fold) than that of peptides containing three tryptophans at both ends. The distribution of arginine at both ends also increased the uptake efficiency 2.52- and 7.18-fold, compared with arginine distribution at the middle of peptides. According to the obtained results the value of transfer free energies of peptides from the aqueous phase to membrane bilayer could be a good predictor for the cellular uptake efficiency of CPPs.
Breast cancer is the second leading cancer type among people of advanced countries. Various metho... more Breast cancer is the second leading cancer type among people of advanced countries. Various methods have been used for cancer treatment such as chemotherapy and radiotherapy. In the present study we have designed and synthesized a new group of drug delivery systems (DDS) containing a new class of Cell Penetrating Peptides (CPPs) named Peptide Amphiphiles (PAs). Two PAs and anionic peptides were synthesized using solid phase peptide synthesis (SPPS), namely [KW]4, [KW]5, E4 and E8. Then nano-peptides were synthesized by non-covalent binding between PAs and poly anions as [KW]4-E4, [KW]4-E8, [KW]5-E4 and [KW]5-E8. Flow cytometry studies showed that increased chain length of PAs with a higher ratio between hydrophobicity and net charge results in increased intracellular uptake by MCF7 cells after 2h incubation. Moreover, nano-peptides showed greater intracellular uptake compared to PAs. Anti-proliferative assay revealed that by increasing chain length of PAs, the toxicity effect on MCF...
Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficul... more Efficient delivery of therapeutic and diagnostic molecules to the cells and tissues is a difficult challenge. The cellular membrane is very effective in its role as a selectively permeable barrier. While it is essential for cell survival and function, also presents a major barrier for intracellular delivery of cargo such as therapeutic and diagnostic agents. In recent years, cell-penetrating peptides (CPPs), that are relatively short cationic and/or amphipathic peptides, received great attention as efficient cellular delivery vectors due to their intrinsic ability to enter cells and mediate uptake of a wide range of macromolecular cargo such as plasmid DNA (pDNA), small interfering RNA (siRNAs), drugs, and nanoparticulate pharmaceutical carriers. This review discusses the various uptake mechanisms of these peptides. Furthermore, we discuss recent advances in the use of CPP for the efficient delivery of nanoparticles, nanocarriers, DNA, siRNA, and anticancer drugs to the cells. In addition, we have been highlighting new results for improving endosomal escape of CPP-cargo molecules. Finally, pH-responsive and activable CPPs for tumor-targeting therapy have been described.
Uploads
Papers by Samaneh Mohammadi